Comparing clinical presentation, viremia, and immunological factors at various severity presentations in hospitalized children affected by COVID‐19: A cross‐sectional study

Abstract Background and Aims Although SARS‐CoV‐2 infection usually leads to mild COVID‐19 in children, sometimes it causes serious complications, especially in those with underlying diseases. Several factors have been identified in determining disease severity in adults, and limited studies have been conducted in children. The prognostic implications of SARS‐CoV‐2 RNaemia as an important factor in determining disease severity in children are not well understood. Methods In this study, we aimed to prospectively assess the relationship between disease severity and immunological factors and viremia in 47 COVID‐19 hospitalized children. In this research, 76.5% of children experienced mild and moderate COVID‐19, while 23.5% experienced severe and critical forms of the disease. Results The presence of underlying diseases in different groups of pediatric patients differed significantly from each other. On the other hand, clinical symptoms such as vomiting and chest pain as well as laboratory parameters including erythrocyte sedimentation rate were significantly different in different groups of patients. Viremia was seen in only two children, and this had no significant relationship with the severity of COVID‐19. Conclusion In conclusion, our data confirmed that COVID‐19 severity differed in SARS‐CoV‐2 infected children. Some clinical presentation and lab data parameters were different in various presentation of patients. Viremia was not associated with severity in our study.


| INTRODUCTION
The new emerged SARS-CoV-2 infection, which has affected a wide range of adults and children worldwide, belongs to β-coronaviruses and it is respiratory in nature with pulmonary effects although the clinical and disease course varies on a caseby-case basis. 1,2 Generally, children are the main population group affected by viral respiratory infections. However, the pediatric population has not been primarily affected by the pandemic, as was first noted during the first COVID-19 pandemic wave. 3 Children and adolescents who contract SARS-CoV-2 typically experience less severe illness and a lower mortality rate than adults. The most frequent clinical symptoms in newborns and infants are fever (53%-59%) and cough (48%-56%), while the less frequent symptoms are gastrointestinal, neurological, and upper and lower respiratory infection. 4 However, most mortality from SARS-CoV-2 infection has been observed in adult and pediatric patients with underlying medical condition. The most important of these were diabetes, cardiovascular disease, hypertension, and chronic bronchitis. 5 Unlike adults, where old age is an independent risk factor for severity and mortality, children at very young ages are considered a risk factor for severity, although this has recently been questioned, and MIS-c is associated with older age.
Although pediatric cases of COVID- 19 have not revealed a clear pattern of laboratory findings related to disease severity, lymphopenia appears to be a risk factor for severe disease in children.
Immunization history, vitamin D levels, RSV coinfection, and genetic polymorphisms are different factors that play a role in determining the severity of COVID-19 in children. 6 Information on other factors that influence disease severity, such as viral load in children, is limited.
Analysis of SARS-CoV-2 RNA in the nasopharynx, often incorrectly referred to as "viral load," does not show a consistent association with asymptomatic versus symptomatic disease or symptomatic disease severity. In contrast, some studies have shown that there is a direct relationship between the presence of virus in the blood and disease severity in adults, but less information is available on the amount of virus in the blood in children and its relationship to the severity of the disease. 3,[7][8][9][10][11][12][13] Comprehensive and detailed data on pediatric patients are limited or incomplete, even as the number of COVID-19 cases continues to rise worldwide. SARS-CoV-2 infected children often develop Kawasaki-like disease and multiorgan involvement. 14 This study first aimed to evaluate the severity status and outcome of the disease and also to identify the most confounding factors in the morbidity and mortality of pediatric COVID-19affected cases.
The most important factors used to determine the severity of the disease investigated were the paraclinical findings, viremic status, and the patients' underlying disease.

| Patients
In this cross-sectional study, we prospectively followed up 47 pediatric patients from August 23, 2021   Demographic characteristics, initial symptoms, clinical signs, laboratory findings, disease severity, and 60-day mortality rates were recorded and followed by a general physician (Laiba Batool). In this study, the majority of patients received Remdesivir and different types of antibiotics.

| Statistical analysis
The Statistical Package for Social Sciences (SPSS version 18.0, SPSS Inc.) was used for statistical analysis. The normality of the data was assessed using Kolmogorov-Smirnov's test. Correlations between parametric and nonparametric data and severity in different groups were assessed using one-way analysis of variance (ANOVA) and Kruskal-Wallis test, respectively. The results were presented in terms of mean ± Standard deviation (±SD).

| RESULTS
To validate the primary objective of this study, the relationship between clinical severity and lab data as well as viremia was analyzed.
Forty-seven patients (25 males, 22 females) were followed for 2 months during the outbreak of the Delta virus strain in Iran. The patients included in the study ranged in age from 15 days to 17 years, with a mean of 9.78 years (SD ± 5.73). As shown in Table 1  analysis showed that the longer the length of hospitalization, the higher the rate of this respiratory infection.
As shown in Table 3, death was observed in two infants with sever underlying disease. Both cases were hospitalized in the ICUs.
The first was an infant with Niemann-Pick who had frequent seizures and the second case was a diabetic patient.  Note: p-value for difference between the four groups were obtained by Kruskal-Wallis test and one-way ANOVA for nonparametric data and parametric data, respectively. p-value ≤ 0.05 was significant. Bold values are statistically significant. a D-Dimer was tested in one severe and three critical patients.

| DISCUSSION
b Ferritin was checked just in two critical patients.
showed that 27% of pediatric COVID-19 patients had RNemia. 17 In almost all relevant studies, serum/plasma RNAemia was associated with worse clinical outcomes, the need for supplemental oxygen, the need for PICU care, and longer hospital stay such in our study.
Since the current study had a relatively low number of severe COVID-19 cases and the patients were sampled only at baseline at enrollment, the number of viremia cases was low.
COVID-19 symptoms can range from mild fever to ARDS, making diagnosis, prognosis, and further surveillance difficult. In the current study, some series of points played a role in determining the severity of COVID-19 disease. The most important of these were ventilator use, oxygen with reservoir, vasoactive drug use, and IVIG or corticosteroid therapy. 18 In our study, 76.5% of children experienced mild and moderate COVID-19 (59.5% and 17%, respectively), while 23.5% experienced severe and critical forms of the disease (17% and 6.5%). Our data were consistent with those of other studies. 19,20 The results showed that the most common clinical symptoms of COVID-19 in children were fever, cough, general weakness, diarrhea, abdominal pain, and malaise, which ranged from 17% to 57%, respectively and they were consistent with those of other studies. 21 In contrast to many studies in adults, 8,9 this research did not find a significant association between disease severity and viremia.
However, the data are consistent with statistics from other studies on children. 16 The most important reason for the differences in these cases is Fortunately, in the current study, a 60-day mortality rate was not significant even in the presence of different complications in a high percentage of patients. However, the current study reports only two deaths (4%) in infants with a complicated underlying medical condition. A study by Pourakbari and colleagues found a pediatric mortality rate of 10%. 24 In the current study, as with others, an underlying medical condition appears to be a key factor in determining COVID-19 disease in children, but there is a lack of evidence to judge the importance and strength of our findings; therefore, it suggests more research. 25 The small sample size of our study is a main limitation, especially the sample size of patients with SARS-CoV-2 viremia, which may affect the statistical results.

| CONCLUSION
Our data confirmed that the severity of COVID-19 varied among children infected with SARS-CoV-2 and was low, as in other studies.
Dyspnea, vomiting, chest pain, and chest abnormalities were critical elements that occurred significantly more frequently in critically ill Heart diseases --2 a 2 Nervous diseases --1 b 1 2

CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.

ETHICS STATEMENT
The project has been approved by Shiraz University of Medical